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Article: Is Endothelial Activation a Critical Event in Thrombotic Thrombocytopenic Purpura?

Cauchois, Raphael / Muller, Romain / Lagarde, Marie / Dignat-George, Françoise / Tellier, Edwige / Kaplanski, Gilles

2023 Volume 12, Issue 3

Abstract: Thrombotic thrombocytopenic purpura (TTP) is a severe thrombotic microangiopathy. The current pathophysiologic paradigm suggests that the ADAMTS13 deficiency leads to Ultra Large-Von Willebrand Factor multimers accumulation with generation of ... ...

Abstract	Thrombotic thrombocytopenic purpura (TTP) is a severe thrombotic microangiopathy. The current pathophysiologic paradigm suggests that the ADAMTS13 deficiency leads to Ultra Large-Von Willebrand Factor multimers accumulation with generation of disseminated microthrombi. Nevertheless, the role of endothelial cells in this pathology remains an issue. In this review, we discuss the various clinical, in vitro and in vivo experimental data that support the important role of the endothelium in this pathology, suggesting that ADAMTS13 deficiency may be a necessary but not sufficient condition to induce TTP. The "second hit" model suggests that in TTP, in addition to ADAMTS13 deficiency, endogenous or exogenous factors induce endothelial activation affecting mainly microvascular cells. This leads to Weibel-Palade bodies degranulation, resulting in UL-VWF accumulation in microcirculation. This endothelial activation seems to be worsened by various amplification loops, such as the complement system, nucleosomes and free heme.
Language	English
Publishing date	2023-01-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm12030758
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Article ; Online: Factors associated with the decision of a French hospital to report child abuse to judicial rather than administrative authorities.

Bailhache, Marion / Lerole, Adeline / Lagarde, Marie / Richer, Olivier

Archives de pediatrie : organe officiel de la Societe francaise de pediatrie

2021 Volume 28, Issue 5, Page(s) 360–365

Abstract: Objectives: Two independent sectors manage the child protection system in France: judicial and administrative protection. The choice between judicial or administrative reporting depends on the seriousness of the case. The goal of this study was to ... ...

Abstract	Objectives: Two independent sectors manage the child protection system in France: judicial and administrative protection. The choice between judicial or administrative reporting depends on the seriousness of the case. The goal of this study was to determine the characteristics associated with the decision in a French pediatric hospital to report child abuse to judicial instead of administrative authorities. Methods: A retrospective study was conducted. Participants were all the children (n=83) who were admitted from 2017 to 2018 to the emergency department (ED) and the general ward of a pediatric university hospital in France, and were reported for suspicion of child abuse by the professional teams. The children who were suspected victims of sexual abuse were excluded. Multivariate logistic regressions were used. Results: A total of 47 children were reported to judicial authorities, and 36 to administrative authorities. Their median age was 7 years. Suspicion of physical abuse (odds ratio [OR]: 21.2; 95% confidence interval [CI]: 4.5-99.1), cases reported by the pediatric ward team (OR: 9.1; 95% CI: 1.9-43.6), adult person different from parents who accompanied the child to the ED (OR: 5.8; 95% CI: 1.2-28.6), and perception of parental behavior as inappropriate and non-cooperative (OR: 6.6; 95% CI: 1.4-29.6) were associated with a higher risk of the case being reported to judicial authorities. Data were often unavailable for parental health issues, history of child abuse, and intimate partner violence. Conclusion: Some factors associated with the choice of report type were most likely quite subjective. Better documentation and standardization are needed.
MeSH term(s)	Adolescent ; Child ; Child Abuse ; Child Protective Services/methods ; Child, Preschool ; Cross-Sectional Studies ; Decision Making ; Female ; France ; Hospitals/standards ; Hospitals/statistics & numerical data ; Humans ; Judicial Role ; Male ; Odds Ratio ; Qualitative Research ; Retrospective Studies ; Risk Factors
Language	English
Publishing date	2021-05-14
Publishing country	France
Document type	Journal Article
ZDB-ID	1181947-9
ISSN	1769-664X ; 0929-693X
ISSN (online)	1769-664X
ISSN	0929-693X
DOI	10.1016/j.arcped.2021.04.007
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Article ; Online: Do Victims of Abusive Head Trauma Visit Emergency Departments More Often Than Children Hospitalized for Fever? A Case-Control Study.

Bailhache, Marion / Lafagne, Ambre / Lagarde, Marie / Richer, Olivier

Pediatric emergency care

2021 Volume 38, Issue 1, Page(s) e310–e315

Abstract: Objective: During the first years of life, infant crying is a common trigger of abusive head trauma (AHT). Emergency department (ED) use by AHT victims before visits for child abuse symptoms is not well known, particularly for infant crying. Furthermore, ...

Abstract	Objective: During the first years of life, infant crying is a common trigger of abusive head trauma (AHT). Emergency department (ED) use by AHT victims before visits for child abuse symptoms is not well known, particularly for infant crying. Furthermore, diagnosis could be missed. In the same period, fever is a common reason for hospitalization unconnected with AHT. The main goal of our study was to compare the ED use by AHT victims before visits for child abuse symptoms and by children of the same age hospitalized for fever. Methods: We conducted a retrospective case-control study from 2011 to June 2018 in a French hospital. We compared cases of AHT selected using the International Classification of Diseases and control subjects hospitalized in the general pediatric unit for fever without immunodeficiency matched in age. Univariate and multivariate analyses were performed. Results: Among the 75 victims of AHT, 5 had at least 1 previous ED visit not linked with abuse. None had visited for infant crying. Among the control subjects, 34 had at least 1 previous ED visit, including 6 for infant crying. Among the 57 dyads of controls and cases living in the hospital's area, the controls had significantly more previous ED visits than the cases (P < 0.001). There were more male infants among the cases (72% vs. 55%, P = 0.033). Conclusions: Our study suggests that AHT victims had no more ED visits before visits for child abuse symptoms, particularly not for infant crying.
MeSH term(s)	Case-Control Studies ; Child ; Child Abuse/diagnosis ; Craniocerebral Trauma/diagnosis ; Craniocerebral Trauma/epidemiology ; Emergency Service, Hospital ; Hospitalization ; Humans ; Infant ; Male ; Retrospective Studies
Language	English
Publishing date	2021-01-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	632588-9
ISSN	1535-1815 ; 0749-5161
ISSN (online)	1535-1815
ISSN	0749-5161
DOI	10.1097/PEC.0000000000002264
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Article ; Online: Mortality, cardiac and cerebral damages reduction by IL-1 inhibition in a murine model of TTP.

Muller, Romain / Cauchois, Raphael / Lagarde, Marie / Roffino, Sandrine / Genovesio, Cecile / Fernandez, Samantha / Hache, Guillaume / Guillet, Benjamin / Kara, Yeter / Marlinge, Marion / Lenting, Peter J / Poullin, Pascale / Dignat-George, Françoise / Tellier, Edwige / Kaplanski, Gilles

Blood

2024

Abstract: Thrombotic thrombocytopenic purpura (TTP), a rare but fatal disease if untreated, is due to alteration in Von Willebrand factor cleavage resulting in capillary microthrombi formation and ischemic organ damage. Interleukin-1 (IL-1), has been shown to ... ...

Abstract	Thrombotic thrombocytopenic purpura (TTP), a rare but fatal disease if untreated, is due to alteration in Von Willebrand factor cleavage resulting in capillary microthrombi formation and ischemic organ damage. Interleukin-1 (IL-1), has been shown to drive sterile inflammation following ischemia and could play an essential contribution to post-ischemic organ damage in TTP. Our objectives were to evaluate IL-1 involvement during TTP and to test the efficacy of the recombinant IL-1 receptor antagonist, anakinra, in a murine TTP model. We retrospectively measured plasmatic IL-1 concentrations in TTP patients and controls. TTP patients exhibited elevated plasma IL-1α and β concentrations, which correlated with disease course and survival. In a TTP mouse model, we administered anakinra (IL-1 inhibitor) or placebo for 5 days and evaluated the efficacy of this treatment. Anakinra significantly reduced mortality of mice (P<0.001). Anakinra significantly decreased TTP-induced cardiac damages as assessed by blood troponin concentrations, evaluation of left ventricular function by echocardiography, [18F]FDG PET of myocardial glucose metabolism, and cardiac histology. Anakinra also significantly reduced brain TTP-induced damages, evaluated through blood PS100b concentrations, nuclear imaging and histology. We finally showed that IL-1α and β trigger endothelial degranulation in vitro, leading to the release of Von Willebrand factor. In conclusion, Anakinra significantly reduced TTP mortality in a pre-clinical model of the disease by inhibiting both endothelial degranulation and post-ischemic inflammation, supporting further evaluations in humans.
Language	English
Publishing date	2024-04-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023021974
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Article ; Online: Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity.

Tellier, Edwige / Widemann, Agnès / Cauchois, Raphaël / Faccini, Julien / Lagarde, Marie / Brun, Marion / Robert, Philippe / Robert, Stéphane / Bachelier, Richard / Poullin, Pascale / Roose, Elien / Vanhoorelbeke, Karen / Coppo, Paul / Dignat-George, Françoise / Kaplanski, Gilles

Haematologica

2023 Volume 108, Issue 4, Page(s) 1127–1140

Abstract: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by a severe ADAMTS13 deficiency due to the presence of anti-ADAMTS13 auto-antibodies, with subsequent accumulation of circulating ultra-large von Willebrand factor (VWF) ... ...

Abstract	Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by a severe ADAMTS13 deficiency due to the presence of anti-ADAMTS13 auto-antibodies, with subsequent accumulation of circulating ultra-large von Willebrand factor (VWF) multimers. The role of endothelial cell activation as a trigger of the disease has been suggested in animal models but remains to be demonstrated in humans. We prospectively obtained plasma from the first plasma exchange of 25 patients during iTTP acute phase. iTTP but not control plasma, induced a rapid VWF release and P-selectin exposure on the surface of dermal human micro-vascular endothelial cell (HMVEC-d), associated with angiopoietin-2 and endothelin-1 secretion, consistent with Weibel-Palade bodies exocytosis. Calcium (Ca2+) blockade significantly decreased VWF release, whereas iTTP plasma induced a rapid and sustained Ca2+ flux in HMVEC-d which correlated in retrospect, with disease severity and survival in 62 iTTP patients. F(ab)'2 fragments purified from the immunoglobulin G fraction of iTTP plasma mainly induced endothelial cell activation with additional minor roles for circulating free heme and nucleosomes, but not for complement. Furthermore, two anti-ADAMTS13 monoclonal antibodies purified from iTTP patients' B cells, but not serum from hereditary TTP, induced endothelial Ca2+ flux associated with Weibel-Palade bodies exocytosis in vitro, whereas inhibition of endothelial ADAMTS13 expression using small intering RNA, significantly decreased the stimulating effects of iTTP immunoglobulin G. In conclusion, Ca2+-mediated endothelial cell activation constitutes a "second hit" of iTTP, is correlated with the severity of the disease and may constitute a possible therapeutic target.
MeSH term(s)	Animals ; Humans ; Purpura, Thrombotic Thrombocytopenic ; Calcium ; von Willebrand Factor/metabolism ; Immunoglobulin G ; ADAMTS13 Protein ; Patient Acuity
Chemical Substances	Calcium (SY7Q814VUP) ; von Willebrand Factor ; Immunoglobulin G ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2023-04-01
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2022.280651
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Article ; Online: Clinicians need to decrease antibiotic use in previously healthy infants hospitalised with bronchiolitis.

Bailhache, Marion / Bloudeau, Emilie / Richer, Olivier / Pillet, Pascal / Lagarde, Marie

Acta paediatrica (Oslo, Norway : 1992)

2017 Volume 107, Issue 3, Page(s) 538–539

MeSH term(s)	Anti-Bacterial Agents/administration & dosage ; Bronchiolitis/diagnosis ; Bronchiolitis/drug therapy ; Case-Control Studies ; Cohort Studies ; Drug Utilization/statistics & numerical data ; Female ; France ; Hospitalization/statistics & numerical data ; Hospitals, University ; Humans ; Infant ; Logistic Models ; Male ; Medical Overuse/prevention & control ; Multivariate Analysis ; Retrospective Studies ; Severity of Illness Index
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2017-12-18
Publishing country	Norway
Document type	Journal Article
ZDB-ID	203487-6
ISSN	1651-2227 ; 0365-1436 ; 0803-5253
ISSN (online)	1651-2227
ISSN	0365-1436 ; 0803-5253
DOI	10.1111/apa.14168
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Article ; Online: Macrophage IL-1β-positive microvesicles exhibit thrombo-inflammatory properties and are detectable in patients with active juvenile idiopathic arthritis.

Cambon, Audrey / Rebelle, Charlotte / Bachelier, Richard / Arnaud, Laurent / Robert, Stéphane / Lagarde, Marie / Muller, Romain / Tellier, Edwige / Kara, Yéter / Leroyer, Aurélie / Farnarier, Catherine / Vallier, Loris / Chareyre, Corinne / Retornaz, Karine / Jurquet, Anne-Laure / Tran, Tu-Anh / Lacroix, Romaric / Dignat-George, Françoise / Kaplanski, Gilles

Frontiers in immunology

2023 Volume 14, Page(s) 1228122

Abstract: Objective: IL-1β is a leaderless cytokine with poorly known secretory mechanisms that is barely detectable in serum of patients, including those with an IL-1β-mediated disease such as systemic juvenile idiopathic arthritis (sJIA). Leukocyte ... ...

Abstract	Objective: IL-1β is a leaderless cytokine with poorly known secretory mechanisms that is barely detectable in serum of patients, including those with an IL-1β-mediated disease such as systemic juvenile idiopathic arthritis (sJIA). Leukocyte microvesicles (MVs) may be a mechanism of IL-1β secretion. The first objective of our study was to characterize IL-1β-positive MVs obtained from macrophage cell culture supernatants and to investigate their biological functions Methods: MVs were purified by serial centrifugations from PBMCs, or THP-1 differentiated into macrophages, then stimulated with LPS ± ATP. MV content was analyzed for the presence of IL-1β, NLRP3 inflammasome, caspase-1, P2X7 receptor, and tissue factor (TF) using ELISA, Western blot, or flow cytometry. MV biological properties were studied Results: THP-1-derived macrophages stimulated with LPS and ATP released MVs, which contained NLRP3, caspase-1, and the 33-kDa precursor and 17-kDa mature forms of IL-1β and bioactive TF. IL-1β-positive MVs expressed P2X7 receptor and released soluble IL-1β in response to ATP stimulation Conclusion: MVs shed from activated macrophages contain IL-1β, NLRP3 inflammasome components, and TF, and constitute thrombo-inflammatory vectors that can be detected in the plasma from active JIA patients.
MeSH term(s)	Humans ; Animals ; Mice ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Inflammasomes/metabolism ; Arthritis, Juvenile/metabolism ; Lipopolysaccharides/pharmacology ; Receptors, Purinergic P2X7/metabolism ; Macrophages/metabolism ; Caspase 1/metabolism ; Adenosine Triphosphate/metabolism
Chemical Substances	NLR Family, Pyrin Domain-Containing 3 Protein ; Inflammasomes ; Lipopolysaccharides ; Receptors, Purinergic P2X7 ; Caspase 1 (EC 3.4.22.36) ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2023-11-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1228122
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Article ; Online: Kinome rewiring during acquired drug resistance in neuroendocrine neoplasms.

Gérard, Corinne / Lagarde, Marie / Poizat, Flora / Oziel-Taieb, Sandrine / Garcia, Vincent / Roche, Catherine / Niccoli, Patricia / Barlier, Anne / Romano, David

Endocrine-related cancer

2020 Volume 28, Issue 1, Page(s) 39–51

Abstract: Although there is evidence of a significant rise of neuroendocrine neoplasms (NENs) incidence, current treatments are largely insufficient due to somewhat poor knowledge of these tumours. Despite showing differentiated features, NENs exhibit therapeutic ... ...

Abstract	Although there is evidence of a significant rise of neuroendocrine neoplasms (NENs) incidence, current treatments are largely insufficient due to somewhat poor knowledge of these tumours. Despite showing differentiated features, NENs exhibit therapeutic resistance to most common treatments, similar to other cancers in many instances. Molecular mechanisms responsible for this resistance phenomenon are badly understood. We aimed at identifying signalling partners responsible of acquired resistance to treatments in order to develop novel therapeutic strategies. We engineered QGP-1 cells resistant to current leading treatments, the chemotherapeutic agent oxaliplatin and the mTor inhibitor everolimus. Cells were chronically exposed to the drugs and assessed for acquired resistance by viability assay. We used microarray-based kinomics to obtain highthroughput kinase activity profiles from drug sensitive vs resistant cells and identified 'hit' kinases hyperactivated in drug-resistant cells, including kinases from FGFR family, cyclin-dependant kinases and PKCs in oxaliplatin-resistant (R-Ox) QGP-1 cells. We then validated these 'hit' kinases and observed that ERK signalling is specifically enhanced in QGP-1 R-Ox cells. Finally, we assessed drug-resistant cells sensitivity to pharmacological inhibition of 'hit' kinases or their signalling partners. We found that FGFR inhibition markedly decreased ERK signalling and cell viability in QGP-1 R-Ox cells. These results suggest that the FGFR/ERK axis is hyperactivated in response to oxaliplatin-based chemotherapeutic strategy. Thus, this sensitive approach, based on the study of kinome activity, allows identifying potential candidates involved in drug resistance in NENs and may be used to broadly investigate markers of NENs therapeutic response.
MeSH term(s)	Aged ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Drug Resistance, Neoplasm ; Female ; Humans ; Male ; Middle Aged ; Neuroendocrine Tumors/drug therapy ; Proteomics/methods
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2020-10-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1530/ERC-19-0142
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Zs.A 4192: Show issues

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Article ; Online: Delayed hemolytic transfusion reaction in children with sickle cell disease: first 5-year retrospective study in mainland France.

Falguière, Claire / Allali, Slimane / Khazem, Bassem / Kamdem, Annie / Arnaud, Cécile / Belloy, Marie / Guitton, Corinne / Odièvre, Marie-Hélène / Pertuisel, Sophie / Dumesnil, Cecile / Guillaumat, Cécile / Garrec, Nathalie / Gauthier, Alexandra / Mahe, Perrine / Soussan-Banini, Valerie / Le-Carrer, Laure / Merlin, Etienne / David, Audrey / Pellegrino, Beatrice /

Paillard, Catherine / Brasme, Jean-Francois / Lagarde, Marie / Pirenne, France / Pondarre, Corinne

Haematologica

2023 Volume 108, Issue 3, Page(s) 889–894

MeSH term(s)	Child ; Humans ; Retrospective Studies ; Anemia, Sickle Cell/epidemiology ; Anemia, Sickle Cell/therapy ; Transfusion Reaction/epidemiology ; France/epidemiology ; Hemolysis ; Isoantibodies
Chemical Substances	Isoantibodies
Language	English
Publishing date	2023-03-01
Publishing country	Italy
Document type	Letter
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2022.281050
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Book ; Thesis: Fractures de l'humerus chez le chien et le chat

Lagarde, Marie-Annette

une étude rétrospective de 265 cas

1993

Author's details	par Marie-Annette Lagarde
Language	Undetermined
Size	111 S, Ill
Document type	Book ; Thesis
Thesis / German Habilitation thesis	@Toulouse, Ecole Nat. Vét., Diss. : 1993
Database	Special collection on veterinary medicine and general parasitology

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